Out Of The Pipeline

Intramuscular naltrexone

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Targeting adherence in alcohol dependency treatment


 

References

A long-acting, intramuscular (IM) naltrexone formulation—which at press time awaited FDA approval (Table)—could improve adherence to alcohol dependency pharmacotherapy.

Oral naltrexone can reduce alcohol consumption1 and relapse rates,1,2 but patients often stop taking it3 and increase their risk of relapse.2 Once-daily dosing, inconsistent motivation toward treatment, and cognitive impairment secondary to chronic alcohol dependence often thwart oral naltrexone therapy.

By contrast, IM naltrexone surmounts most compliance issues because you or a clinical assistant administer the drug. Short-term side effects—such as nausea for 2 days—are less likely to affect adherence because the medication keeps working weeks after side effects abate. This gives you time before the next dose to reassure the patient and gives the patient the benefits of continued treatment.

Table

IM naltrexone: Fast facts

Drug brand name: Vivitrol
Class: Opioid antagonist
Prospective indication: Alcohol dependence
FDA action: Issued approvable letter Dec. 28, 2005
Manufacturer: Alkermes
Dosing forms: 380 mg suspension via IM injection
Recommended dosage: 380 mg once monthly
Estimated date of availability: Spring 2006

How naltrexone works

Alcohol stimulates release of endogenous opioids, which in turn stimulate release of dopamine, which mediates reinforcement.4 Opioid receptor stimulation not associated with dopamine also reinforces alcohol use.5 Persons vulnerable to alcohol dependence generally have lower basal levels of opioid secretion and are stimulated at higher levels.6 Opioids also increase dopamine by inhibiting GABA neurons, which suppress dopamine release when uninhibited.

As an opioid antagonist, naltrexone prevents opioids from binding with μ-opioid receptors and modulates dopamine production. This may make drinking less “rewarding” and may reduce craving triggered by conditioned cues associated with alcohol use.

IM naltrexone is packaged in biodegradable microspheres that slowly release naltrexone for 1 month after injection. The microspheres are made of a polyactide-co-glycolide polymer used in other extended-release drugs and in absorbable sutures.

Pharmacokinetics

IM naltrexone plasma levels peak 2 to 3 days after injection, then decline gradually over 30 days. Oral naltrexone dosed at 50 mg/d for 30 days—a cumulative dose of 1,500 mg/month—produces daily peak plasma levels of approximately 10 ng/mL and troughs approaching zero. A once-monthly IM naltrexone injection results in a lower net dose but more-sustained naltrexone levels.

Efficacy

IM naltrexone significantly reduced heavy drinking among alcohol-dependent patients in a phase 3 randomized, placebo-controlled, multicenter trial.7 Actively drinking adults who met DSM-IV criteria for alcohol dependence (N=624) received IM naltrexone, 190 or 380 mg, or placebo every 4 weeks for 6 months. Oral naltrexone lead-in doses were not given. All patients also received 12 sessions of standardized supportive psychosocial therapy during the study.

The primary efficacy measure was event rate of heavy drinking, defined as number of heavy drinking days (≥5 drinks/day for men, ≥4 drinks/day for women) divided by number of days in the study. An event rate ratio (treatment-group to placebo-group event rate) was then estimated over time, taking into account patients who discontinued the study.

After 6 months, event rate of heavy drinking fell 25% among patients receiving 380 mg of IM naltrexone and supportive therapy, compared with patients receiving placebo and supportive therapy (P=0.02). That rate decreased 17% among patients who received 190 mg of IM naltrexone compared with placebo, but the difference between the two treatment groups was not statistically significant (P=0.07).

The median number of heavy drinking days per month decreased substantially across 6 months among all study groups. The decrease was more substantial among patients taking IM naltrexone, 380 mg, than among the placebo group (Figure).

Roughly 8% of patients abstained from drinking for 7 days before entering the study. Among patients who received 380 mg of IM naltrexone:

  • those who were abstinent before the study had an 80% greater reduction in event rate of heavy drinking compared with placebo
  • nonabstinent patients showed a 21% greater reduction in event rate of heavy drinking compared with placebo.

These findings suggest that IM naltrexone is more effective in persons abstaining from drinking but can also help actively drinking patients.

IM naltrexone also reduced heavy drinking among patients who entered a 1-year open-label extension study after completing the 6-month study.8 Drinking reductions were greater among patients who received 380 mg of naltrexone during both the 6-month and 1-year trials than among those who received placebo for 6 months and were switched to naltrexone, 380 mg, in the 1-year extension.

Figure Median heavy drinking days after 6 months of IM naltrexone or placebo


Source: Reference 7

Tolerability

IM naltrexone was well-tolerated in the phase 3 trial.7 Most-common adverse effects included

  • nausea (reported by 33% of patients receiving 380 mg [n=205] and 25% of those receiving 190 mg [n=210])
  • headache (22%, 16%)
  • fatigue (20%, 16%).

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